Khalid, Amina; (2006) Characterisation of spray-dried trehalose/alkaline phosphatase formulations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Despite the advances in biotechnology the formulation of protein based medicine is limited. This is because proteins are not stable molecules. Generally protein formulations are produced from freeze drying but solid formulations can also be obtained through spray drying. These processes can have detrimental effects on protein stability. Disaccharides, particularly trehalose, are common excipients that are examined in protein formulations, as they may act as protectants for proteins in the solid state. The aim of this thesis was to prepare spray-dried trehalose/alkaline phosphatase particles and investigate the properties of trehalose in the presence of a protein. Furthermore, the influences of acetone and surfactants on the properties of trehalose are also examined. The tendency of trehalose to convert into different physical forms was studied by differential scanning calorimetry (DSC), as it is believed to be a key property in its ability to stabilise proteins. Transformation pathways were determined depending on heating rates and sample size and indicated that these could occur concurrently at varying degrees. The spray dryer, SDMicro™ was commissioned and evaluated by processing amorphous trehalose. Amorphous trehalose samples were studied with regard to morphology and water sorption behaviour. The NIR data collected during the water sorption studies were compared to the different physical forms of trehalose. It could be concluded that regardless of the spray drying process, all amorphous trehalose batches crystallised to the dihydrate form when exposed to increased humidity. The NIR spectra also revealed that some batches proceeded to the dihydrate form via the anhydrous forms and confirmed the finding of the DSC study. Spray-dried samples of trehalose were prepared with alkaline phosphatase and surfactants. These formulations showed significant differences in particle morphology as a function of protein concentration, acetone and surfactants. The stability of the samples was investigated by exposure to increased humidity and NIR spectra were also recorded to study the changes in trehalose during storage. The crystallisation process of trehalose in the spray-dried samples could be observed but no band could be assigned for protein degradation. This was due to the low protein content in the formulations. The degradation was followed by activity assays. The morphology of the spray-dried AP particles could be correlated to the surface properties. The surface properties of these particles were studied with regards to their morphology, glass transitions and surface energies. The AP particles prepared with surfactant, showed correlation between protein degradation and the crystallisation of trehalose.

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